SSR69071, an elastase inhibitor, reduces myocardial infarct size following ischemia-reperfusion injury

Neutrophil elastase contributes to the severity of cardiac damage following coronary ischemia and reperfusion. We evaluated the effects of 2-(9-(2-piperidinoethoxy)-4-oxo-4H-pyridol[1,2-a]pyrimidin-2-yloxymethyl)-4-(1-methyethyl)-6-methoxy-1,2-benzisothiazol-3(2H)-one-1,1-dioxide hemihydrate (SSR69071), a novel, potent and selective inhibitor of neutrophil elastase, on infarct size in anaesthetized rabbits subjected to coronary artery occlusion for 30 min followed by reperfusion for 120 min. SSR69071 (3 mg/kg i.v.) reduced cardiac infarct size when administered before ischemia (- 39%, P<0.05) or just prior to reperfusion (- 37%, P<0.05). Subsequent experiments using the latter administration protocol confirmed the ability of SSR69071 (1 and 3 mg/kg i.v.) to reduce infarct size. This cardioprotective activity was associated with inhibition of cardiac elastase. (C) 2003 Elsevier Science B.V. All rights reserved.